Summary: Tat protein of HIV-1 is essential for virus replication and progression of HIV disease. Recently, we reported two critical domains, Tat21-40 and Tat53-68 in HIV-1 group M and Tat9-20 in HIV-1 group O subtypes, of the HIV-Tat proteins that mediate pathogenesis. Effective induction by cysteine-rich (Tat21-40) and basic domain (Tat53-68) of nuclear factor-kB-mediated HIV replication indicates that these short sequences are sufficient to promote HIV infection. These findings are potentially important to understand the progression of HIV pathogenesis and in the development of potential therapeutic applications. We have now synthesized a synthetic construct (Tat-MPC) comprising functional Tat sequences. This construct is highly immonogenic. The anti-Tat MPC antibodies efficiently inhibited Tat-induced viral activation in monocytes infected with HIV-BaL as well as with various clinical isolates, and substantially reduced Tat-mediated cytopathic effects in infected cells. This epitope-specific synthetic construct will be tested for its ability to induce immune response and reduce progression of HIV disease in HIV-infected non-human primates. Furthermore, because of critical involvement of HIV-Tat protein in progression of HIV disease, we also plan to examine the molecular mechanisms involved in HIV-Tat-mediated immune dysregulation and develop diagnostic tools for the detection of extracellular Tat protein in blood/blood products. These continued studies may also help defining a role of HIV-Tat in seropositive non-progressors who have high titer of anti-Tat antibodies with a substantially low viral load.